PROJECT SUMMARY The ?4 allele of apolipoprotein E (apoE4) is the most important genetic risk factor for late-onset sporadic Alzheimer's disease (LOAD). ApoE is a secreted glycoprotein that binds to a number of single-pass transmembrane receptors of the low-density-lipoprotein receptor family, including apoER2 (official gene name = LRP8). Interestingly, human apoER2 is subject to a high degree of alternative splicing events and notably one of the top 10 of all neuronal genes related to exon-skipping splicing events. We have identified and confirmed the expression of a large number of alternatively spliced apoER2 receptors in human brain, many of which contain a different number of ligand binding domains which alter the binding of human apoE protein to apoER2. However, the functional consequences of differential apoE-apoER2 interactions, downstream receptor signaling and neuronal function for these naturally occurring human apoER2 splice variants remain incompletely understood. The goal of this proposal is to define the functional consequences of specific apoE- apoER2 interactions that could have major implications for our understanding of synaptic plasticity associated with learning and memory and the role of apoE4 in LOAD.